FRI0268 Glucocorticoid-induced leucine zipper (GILZ) represents a checkpoint limiting type i interferon (IFN) production in sle

Background Glucocorticoids (GC) remain the mainstay of treatment in Systemic Lupus Erythematosus (SLE). Type I interferons (IFN), produced by plasmacytoid dendritic cells (pDC) in response to Toll-Like receptors (TLR) ligands, are critical to SLE pathogenesis, but are not suppressed by GC. Glucocorticoid-Induced Leucine Zipper (GILZ) is an endogenous anti-inflammatory protein induced by GC. Beaulieu et al., 2010 However, whether GILZ regulates IFN production in SLE is not known. Objectives To test the hypothesis that GILZ inhibits the production of Type I IFN in SLE. Methods We performed in vitro analysis on pDC and bone marrow-derived DC (BMDC), and in vivo studies, of WT and GILZ-/- mice using stimuli of TLR7 (Imiquimod), TLR7/8 (Resiquimod) and TLR9 (CpG). IFN was measured using a IFN luciferase assay, and other cytokines with ELISA. IFN-stimulated gene signatures (ISG) were measured using qPCR. To determine whether GILZ regulates IFN in human SLE, we mined a public gene expression dataset GSE10325. Becker et al., 2013 Results Deletion of GILZ resulted in excess pDC secretion of IFN in response to TLR7 (p=0.0012) and TLR9 (p=0.01) stimulation, and BMDC secretion of IFN, IL-6 and TNFα in response to TLR7 (p=0.0039, 0.017, 0.033), TLR7/8 (p=0.001, Conclusions GILZ is an endogenous regulator of increased IFN production in response to TLR stimulation in vitro and in mice, and is negatively correlated with ISG in human SLE. This suggests that GILZ negatively regulates type I IFN production and GILZ based therapy may be a potential therapeutic strategy that could reduce steroid dependence in SLE. References [1] Beaulieu E, Ngo D, Santos L, Yang YH, Smith M, Jorgensen C, … Morand EF. Glucocorticoid-induced leucine zipper is an endogenous antiinflammatory mediator in arthritis. Arthritis Rheum2010;62(9):2651–2661. doi:10.1002/art.27566 [2] Becker AM, Dao KH, Han BK, Kornu R, Lakhanpal S, Mobley AB, … Davis LS. SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature. PLoS One2013;8(6):e67003. doi:10.1371/journal.pone.0067003 Acknowledgements NHMRC Disclosure of Interest None declared